A maximally comprehensive analysis of the autoimmune response of the immune system is necessary for developing efficient serodiagnostic agents and therapeutic agents for neurological autoimmune diseases. The serodiagnosis of autoimmune diseases is based on detection of autoantibodies which circulate in the blood and are specifically directed against immunogenic constituents (antigens) of autologous proteins. These antigens are also the sites of action of preventive and therapeutic strategies for autoimmune diseases. Knowledge of these antigens therefore permits the development of methods for the specific diagnosis and therapy of inflammatory neurological diseases.
Inflammatory neurological diseases, and especially multiple sclerosis (MS), are widespread diseases. According to statements by the WHO, multiple sclerosis is the commonest neurological disease in young adults around the world, with a prevalence of about 1:800 in Europe and North America. The chronic inflammatory disease of the nervous system, which appears for the first time in patients between 15 and 40 years of age, leads to a demyelinization of dendrites of the central nervous system (CNS). This results in a progressive paralysis of the muscles, losses of sensitivity and psychological disorders. Both the clinical course and the pathology of the cerebral disease are extremely heterogeneous (Lucchinetti et al., 2000 Ann Neurol 47, 707), The disease has either a chronic progressive or episodic course. General neurological symptoms appear initially and can be differentiated only with difficulty from other neurological diseases.
The etiology of the neurological autoimmune diseases and especially of MS has not been completely elucidated as yet, despite intensive research. An important role is ascribed to genetic and immunological and viral/bacterial factors (Kalman et al., 1999, Biomed Pharmac 53, 358; Lucchinetti et al., 2001, Curr Opin Neurol 14, 259; Kurtzke, 2001, J Clin Epidemiol 54, 1). A crucial role is, however, played by autoimmune processes, and various hypotheses concerning the immune dysregulation have been suggested. Thus, for example, the loss of regulatory mechanisms of autoreactive T cells has been described. The pathogenesis of MS lesions (Lucchinetti et al., 2000, Ann Neurol 47, 707) additionally supports the importance of autoimmune processes in the course of the disease. The reasons for the autoimmunity might be for example the similarity of viral antigens to encephalitogenic antigens (“Molecular mimicry”) or traumatic tissue death (Levin et al., 2002, Nat Med 8, 509; Ludewig et al., 2004, J Exp Med 200, 837) as underlying mechanism. The significance of the immune dysregulation in inflammatory neurological diseases is additionally supported by numerous experiments in model organisms in which an “experimental autoimmune encephalitis” (EAE) can be induced by autoimmunological processes ('t Hart et al., 2003, Curr Opin Neurol 18, 375).
The diagnosis of neurological autoimmune diseases and of MS in particular is currently a great problem. The first symptoms such as, for example, vision or coordination impairments and signs of paralysis and deafness apply to numerous neurological diseases, and differential diagnosis from autoimmune diseases is scarcely possible (Schmitt, 2003, Biomed Pharmacother 57, 261). A reliable diagnosis of MS is ultimately obtained only by combination with other criteria such as, for example, the number of inflammatory brain lesions which are obtained with the aid of MRI spectroscopy (magnetic resonance imaging), or analysis of oligoclonal IgG bands in the CSF. A rapid and reliable diagnosis using serum or urine is not at present possible, although various markers have been analyzed for their diagnostic power (Berger et al., 2003, New Engl J Med 349, 139; Chamczuk et al., 2002, J Imm Methods 262, 21; Vojdani et al., 2003, J Int Med 254, 383) and immunological tests in the form of ELISA and RIA are commercially available (e.g. from Diagnostics Systems Laboratory, Dakocytomation). There is as yet furthermore no laboratory diagnostic method which characterizes the course of MS in relation to imminent pathological episodes, and characterizes the course of pathological episodes and determines whether the disease is about to take a more active or aggressive course in patients (e.g. episodic course of the disease to chronic progressive). Ultimately, there is no diagnostic method which gives prognostic indications of possible MS and/or a diagnostic method which characterizes the course of treatment of MS.
A disease-specific treatment of MS has not been established to date. The treatment of MS is currently predominantly symptomatic using antiinflammatory medicaments. Steroids and various interferons are employed in particular (Jacobs et al., 2003, J Exp Med 343, 598; EP1289541). In principle, these medicaments reduce the inflammatory immune response through toxic effects on lymphocytes, but do not prevent the further episodic or chronic progressive course of the disease. Other substances currently being tested are statins (US2002159974) and glatiramer acetate, which is said to inhibit T-cell proliferation by competition (Duda et al., 1999, J Clin Invest 105, 987; EP1487783; WO2004078145). In addition, some antigen-specific approaches are currently being analyzed. Attempts to treat MS by T-cell vaccinations are still in the early stages (WO9115225). Therapeutic approaches with various monoclonal antibodies directed against the antigens α4-integrin (Bielekova et al. 2000, Nat Med 6, 1145), CD40 (patent publication: WO03045978) and CD52 (patent publication: EP1455826) are moreover in different clinical phases. It has moreover been possible to test successfully an antigen-specific tolerance therapy in EAE models (Robinson et al., 2003, Nat Biotechn 21, 1033).
It has not been possible to utilize the information obtained to date in order to provide maximally sensitive and specific test methods enabling reliable and generally accepted diagnostic methods using serum for neurological autoimmune diseases, especially multiple sclerosis. Nor has it been possible on the basis of the antigens known to date to establish either an effective preventive or a therapeutic vaccination, although a wide variety of methods have been published, and some substances are still being tested.
There is thus a need for an effective diagnosis, prognosis and therapy of neurological autoimmune diseases, and especially multiple sclerosis.
It was the object of the present invention to provide target structures for a diagnosis, prognosis and therapy of neurological autoimmune diseases such as multiple sclerosis. It was the particular object of the present invention to identify molecular markers which enable differential diagnosis between neurological autoimmune diseases such as multiple sclerosis and other neurological diseases.
This object is achieved according to the invention by the subject matter of the claims.